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Nitric oxide donating prostamides

a prostamide and nitric oxide technology, applied in the field of prostaglandin derivatives, can solve the problems of eye pressure increasing to unhealthy levels, affecting the effect of eye pressure, so as to reduce the level, maintain the pressure, and reduce the eye pressure

Active Publication Date: 2012-01-24
NICOX SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0107]Other features and advantages will be apparent from the specification and claims which describe the invention.

Problems solved by technology

Glaucoma occurs when an imbalance in production and drainage of fluid in the eye (aqueous humor) increases eye pressure to unhealthy levels.
Several side effects are associated with the drugs conventionally used to treat glaucoma.
Topical beta-blockers show serious pulmonary side effects, depression, fatigue, confusion, impotence, hair loss, heart failure and bradycardia.
Topical α-agonists have a fairly high incidence of allergic or toxic reactions; topical cholinergic agents (miotics) can cause visual side effects.

Method used

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  • Nitric oxide donating prostamides
  • Nitric oxide donating prostamides
  • Nitric oxide donating prostamides

Examples

Experimental program
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Effect test

examples

[0130]In the examples described below, unless otherwise indicated, all temperatures are set forth in degrees Celsius and all parts and percentages are by weight. Reagents may be purchased from commercial suppliers, such as Sigma-Aldrich Chemical Company, Acros Organics, or Lancaster Synthesis Ltd. and may be used without further purification unless otherwise indicated. Tetrahydrofuran (THF), methylene chloride (CH2Cl2 or DCM), N,N-dimethylacetamide (DMA), acetonitrile (MeCN or ACN), and N,N-dimethylformamide (DMF) may be purchased from Aldrich in Sure-Seal bottles and used as received. All solvents may be purified using standard methods known to those skilled in the art, unless otherwise indicated. Diethyl ether is abbreviated as Et2O. Ethyl acetate is abbreviated as EtOAc or EA. Trifluoroacetic acid is abbreviated as TFA. Acetic acid is abbreviated as HOAc or AcOH. Trifluoromethanesulfonate, or triflate, is abbreviated as “OTf.” tert-Butoxycarbonyl is abbreviated as BOC. 4-(N,N-Dim...

example a-1

NCX 469

(1S,2E)-3-{(1R,2R,3S,5R)-2-[(2Z)-7-(Ethylamino)-7-oxohept-2-en-1-yl]-3,5-dihydroxycyclopentyl}-1-(2-phenylethyl)prop-2-en-1-yl 4-(Nitrooxy)butanoate (A-1)

[0137]Following an analogous procedure from Bundy, G. L.; Peterson, D. C.; Cornette, J. C.; Miller, W. L.; Spilman, C. H.; Wilks, J. W. J. Med. Chem. 1983, 26, 1089-1099, to a solution of bimataprost (Cayman Chemicals; 200 mg, 0.481 mmol) in dichloromethane (4.8 mL) was added butylboronic acid (55.0 mg, 0.541 mmol). After 1 h at 42° C., some dichloromethane was evaporated and fresh dichloromethane added. This evaporation-fresh solvent addition sequence was repeated 3 times. 4 Å molecular sieves were added and the mixture stirred at 42° C. for 18 h. 4-Bromobutyryl chloride (0.061 mL; 0.53 mL) was added and allowed to stir at ambient temperature for 48 h. The solvent was removed under reduced pressure and the residue dissolved in acetonitrile (2.4 mL). Silver nitrate (163 mg, 0.962 mmol) was added and allowed to stir at ambien...

example b-1

NCX470

(1S,2E)-3-{(1R,2R,3S,5R)-2-[(2Z)-7-(Ethylamino)-7-oxohept-2-en-1-yl]-3,5-dihydroxycyclopentyl}-1-(2-phenylethyl)prop-2-en-1-yl 6-(Nitrooxy)hexanoate (B-1)

Step 1: (5Z)-7-{(6R,7R)-3-Butyl-7-[(1E,3S)-3-hydroxy-5-phenylpent-1-en-1-yl]-2,4-dioxa-3-borabicyclo[3.2.1]oct-6-yl}-N-ethylhept-5-enamide (b-1)

[0146]

[0147]Following an analogous procedure from Bundy, G. L.; Peterson, D. C.; Cornette, J. C.; Miller, W. L.; Spilman, C. H.; Wilks, J. W. J. Med. Chem. 1983, 26, 1089-1099, to a solution of bimatoprost (Cayman Chemicals 16820, Lot 188757; 679 mg, 1.63 mmol) in DCM (10.9 mL) was added butylboronic acid (187 mg, 1.84 mmol). After 1 hour at 42° C., solvent was removed under reduced pressure and dried under high vacuum pump for 2 hours. Fresh DCM was added and stirred at 42° C. for another hour. Solvent was removed and dried under high vacuum pump for 1.5 hour. Fresh DCM was added again and stirred at 42° C. for 16 hours. Solvent was evaporated and dried in vacuum oven at 45° C. for 3...

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PUM

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Abstract

Nitroderivatives of prostaglandins having improved pharmacological activity and enhanced tolerability are described. They can be employed for the treatment of glaucoma and ocular hypertension.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This application is a National Stage entry of International Application No. PCT / IB2009 / 005594, filed May 11, 2009, which claims priority to Provisional Application No. 61 / 052,084, filed May 9, 2008, and Provisional Application No. 61 / 139,333 filed Dec. 19, 2008 the disclosure of the prior applications are hereby incorporated in their entirety by reference.BACKGROUND OF THE INVENTION[0002]The present invention relates to new prostaglandin derivatives. More particularly, the present invention relates to nitrooxyderivatives of prostaglandin amides (also known as prostamides), pharmaceutical compositions containing them and their use as drugs for treating glaucoma and ocular hypertension.[0003]Glaucoma is a disease of the eye characterized by a progressive loss of visual field due to irreversible damage to the optic nerve to the point where, if untreated, may result in total blindness. Glaucoma occurs when an imbalance in production and draina...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K31/04A61K31/16C07C203/04C07C291/00
CPCC07C291/02C07C405/00C07C2101/08C07C2101/02C07C2601/02C07C2601/08A61P27/02A61P27/06
Inventor BENEDINI, FRANCESCABIONDI, STEFANOCHIROLI, VALERIOCHONG, WESLEY KWAN MUNGDONG, LIMINGKRAUSS, ACHIM HANS-PETERNICOLI, FABIOPRASANNA, GANESHVERNIER, WILLIAM FRANCOISYANG, YI
Owner NICOX SA
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